HK3 – Premature Menopause

The association between HK3 (HGNC:4925) and premature menopause (MONDO_0001119) has been evaluated in two independent genetic association studies. In one study conducted in a Chinese Han cohort, 371 women affected by premature ovarian failure and 800 controls were analyzed, and the HK3 SNP rs2278493 demonstrated a statistically significant association with the disease (PMID:22248077). In contrast, a replication study in a Serbian cohort including 197 cases and 552 controls failed to confirm the association with HK3 (PMID:24103315).

The genetic evidence is thus conflicting. The positive association observed in the Chinese study supports a potential role for HK3 in contributing to premature menopause; however, the negative findings in the Serbian cohort reduce overall confidence in this link. No family-based segregation data were provided, and additional affected relative reports are absent, which limits the ability to further substantiate the association.

Given the multifactorial and complex nature of premature menopause, the inheritance pattern appears non‑Mendelian. Moreover, there is a lack of robust functional studies that explore the molecular mechanisms by which HK3 might influence ovarian aging or failure. The current experimental evidence is insufficient to provide a clear pathogenic mechanism.

In summary, the genetic evidence for an association between HK3 and premature menopause remains limited. Although a significant association was reported in one population, the failure of replication in another distinct ethnic group, combined with the absence of supportive functional data, suggests that further studies are necessary before this association can be reliably integrated into clinical decision‑making.

Key take‑home: The conflicting genetic findings underscore the need for additional replication and functional studies to clarify the role of HK3 in the pathogenesis of premature menopause.

References

• Maturitas • 2014 • Ethnic specificity of variants of the ESR1, HK3, BRSK1 genes and the 8q22.3 locus: no association with premature ovarian failure in Serbian women PMID:24103315
• Orphanet journal of rare diseases • 2012 • ESR1, HK3 and BRSK1 gene variants are associated with both age at natural menopause and premature ovarian failure PMID:22248077

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